Encorafenib

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Encorafenib
Encorafenib.svg
Clinical data
Trade names Braftovi
Other namesLGX818
AHFS/Drugs.com Monograph
MedlinePlus a618040
License data
Routes of
administration 		By mouth
Drug class Antineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • Methyl [(2S)-1-{[4-(3-{5-chloro-2-fluoro-3-[(methylsulfonyl)amino]phenyl}-1-isopropyl-1H-pyrazol-4-yl)-2-pyrimidinyl]amino}-2-propanyl]carbamate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C22H27ClFN7O4S
Molar mass 540.01 g·mol−1
3D model (JSmol)
  • C[C@@H](CNc1nccc(n1)c2cn(nc2c3cc(cc(c3F)NS(=O)(=O)C)Cl)C(C)C)NC(=O)OC
  • InChI=1S/C22H27ClFN7O4S/c1-12(2)31-11-16(17-6-7-25-21(28-17)26-10-13(3)27-22(32)35-4)20(29-31)15-8-14(23)9-18(19(15)24)30-36(5,33)34/h6-9,11-13,30H,10H2,1-5H3,(H,27,32)(H,25,26,28)/t13-/m0/s1
  • Key:CMJCXYNUCSMDBY-ZDUSSCGKSA-N

Encorafenib, sold under the brand name Braftovi, is an anti-cancer medication used for the treatment of certain melanoma cancers. It is a small molecule BRAF inhibitor [4] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers. [5]

Contents

The most common (≥25%) adverse reactions include fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia. [6]

Encorafenib was developed by Novartis and Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of people with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. [6] [7]

Medical uses

Encorafenib is indicated in combination with binimetinib, for the treatment of people with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test; [2] in combination with cetuximab, for the treatment of adults with metastatic colorectal cancer with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy; [2] in combination with binimetinib, for the treatment of adults with metastatic non-small cell lung cancer with a BRAF V600E mutation, as detected by an FDA-approved test. [2] [8]

Encorafenib is not indicated for treatment of people with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC. [2]

In December 2024, the FDA granted accelerated approval to encorafenib with cetuximab and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) for people with metastatic colorectal cancer with a BRAF V600E mutation, as detected by an FDA-approved test. [9]

Pharmacology

Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1. [10] This arrests the cell cycle in G1 phase, inducing senescence without apoptosis. [10] Therefore, it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas. [11] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes. [4]

History

Approval of encorafenib in the United States was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 participants with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. [6] Participants were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. [6] Treatment continued until disease progression or unacceptable toxicity. [6]

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review. [6] The median PFS was 14.9 months for participants receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001). [6] The trial was conducted at 162 sites in Europe, North America, and various countries around the world. [7]

Efficacy for encorafenib with cetuximab and mFOLFOX6 was evaluated in BREAKWATER (NCT04607421), an active-controlled, open-label, multicenter trial. [9] Participants were required to have treatment naïve BRAF V600E mutation-positive metastatic colorectal cancer, detected by the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit. [9] Participants were initially randomized 1:1:1 to one of the following treatment arms: encorafenib orally once daily with cetuximab IV infusion every 2 weeks (encorafenib+cetuximab arm); [9] encorafenib orally once daily with cetuximab IV infusion every 2 weeks and mFOLFOX6 every 2 weeks (encorafenib+cetuximab+mFOLFOX6 arm); [9] or mFOLFOX6, FOLFOXIRI (both every 2 weeks) or CAPOX (every 3 weeks)-each with or without bevacizumab (control arm). [9] The trial was subsequently amended to limit randomization (1:1) to the encorafenib +cetuximab+mFOLFOX6 arm and the control arm. [9] Treatment in all arms continued until disease progression, unacceptable toxicity, consent withdrawal, lost to follow-up, or death. [9] The results of the encorafenib + cetuximab + mFOLFOX6 arm compared to the control arm served as the basis of this accelerated approval and are described below. [9]

Clinical trials

Several clinical trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162, [12] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated. [13]

Related Research Articles

<span class="mw-page-title-main">Melanoma</span> Skin cancer originating in melanocytes

Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye.

<span class="mw-page-title-main">Cetuximab</span> Pharmaceutical drug

Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal antibody given by intravenous infusion.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">BRAF (gene)</span> Protein-coding gene in humans

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

<span class="mw-page-title-main">Vemurafenib</span> Targeted cancer drug

Vemurafenib (INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma. It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Trametinib</span> Anticancer medication

Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma and glioma. It is a MEK inhibitor drug with anti-cancer activity. It inhibits MEK1 and MEK2. It is taken by mouth.

A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers.

<span class="mw-page-title-main">Dabrafenib</span> Anti-cancer medication

Dabrafenib, sold under the brand name Tafinlar among others, is an anti-cancer medication used for the treatment of cancers associated with a mutated version of the gene BRAF. Dabrafenib acts as an inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody, more specifically a PD-1 Inhibitor, used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

<span class="mw-page-title-main">Cobimetinib</span> Chemical compound

Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used to treat melanoma and histiocytic neoplasms. Cobimetinib is a MEK inhibitor. Cobimetinib is marketed by Genentech.

<span class="mw-page-title-main">Binimetinib</span> Chemical compound

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib. It was developed by Array Biopharma.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Sacituzumab govitecan</span> Antibody-drug conjugate

Sacituzumab govitecan, sold under the brand name Trodelvy by Gilead Sciences, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer.

V600E is a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600. It is a driver mutation in a proportion of certain diagnoses, including melanoma, hairy cell leukemia, papillary thyroid carcinoma, colorectal cancer, non-small-cell lung cancer, Langerhans cell histiocytosis, Erdheim–Chester disease and ameloblastoma.

<span class="mw-page-title-main">Tucatinib</span> Chemical compound

Tucatinib, sold under the brand name Tukysa, is an anticancer medication used for the treatment of HER2-positive breast cancer. It is a small molecule inhibitor of HER2. It was developed by Array BioPharma and licensed to Cascadian Therapeutics.

<span class="mw-page-title-main">Adagrasib</span> Medication

Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer. Adagrasib is an inhibitor of G12C mutated KRAS GTPase. It is taken by mouth. It is being developed by Mirati Therapeutics.

Lifileucel, sold under the brand name Amtagvi, is an adoptive T cell therapy used for the treatment of melanoma.

References

  1. ↑ "Summary Basis of Decision (SBD) for Braftovi". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. 1 2 3 4 5 "Braftovi- encorafenib capsule". DailyMed. 18 October 2023. Retrieved 6 August 2024.
  3. ↑ "Braftovi EPAR". European Medicines Agency (EMA). 20 September 2018. Retrieved 6 August 2024.
  4. 1 2 Koelblinger P, Thuerigen O, Dummer R (March 2018). "Development of encorafenib for BRAF-mutated advanced melanoma". Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC   5815646 . PMID   29356698.
  5. ↑ Burotto M, Chiou VL, Lee JM, Kohn EC (November 2014). "The MAPK pathway across different malignancies: a new perspective". Cancer. 120 (22): 3446–56. doi:10.1002/cncr.28864. PMC   4221543 . PMID   24948110.
  6. 1 2 3 4 5 6 7 "FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations". U.S. Food and Drug Administration (FDA). 27 June 2018. Archived from the original on 19 December 2019. Retrieved 28 June 2018.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. 1 2 "Drug Trial Snapshot: Braftovi". U.S. Food and Drug Administration (FDA). 16 July 2018. Archived from the original on 19 December 2019. Retrieved 18 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  8. ↑ "FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation". U.S. Food and Drug Administration (FDA). 11 October 2023. Retrieved 11 October 2023.
  9. 1 2 3 4 5 6 7 8 9 "FDA grants accelerated approval". U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, et al. (January 2016). "Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells". Cancer Letters. 370 (2): 332–44. doi:10.1016/j.canlet.2015.11.015. PMID   26586345. S2CID   2550254.
  11. ↑ Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. (July 2012). "A landscape of driver mutations in melanoma". Cell. 150 (2): 251–63. doi:10.1016/j.cell.2012.06.024. PMC   3600117 . PMID   22817889.{{cite journal}}: CS1 maint: overridden setting (link)
  12. ↑ "18 Studies found for: LGX818". Clinicaltrials.gove.
  13. ↑ Clinical trial number NCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)" at ClinicalTrials.gov
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